Low dosage forms of risedronate or its salts

ABSTRACT

Oral dosage forms comprising risedronate or a salt thereof, a chelating agent, and means for effecting delayed release of the risedronate (or salt) immediate release of the oral dosage form to the small intestine of the mammal subject and pharmaceutically effective absorption of the bisphosphonate with or without food or beverages. The present invention substantially alleviates the interaction between the risedronate (or salt) and food or beverages, which interaction results in the active ingredient not being available for absorption. The resulting oral dosage form may thus be taken with or without food. Further, disclosed is delivery of risedronate and the chelating agent to the small intestine, substantially alleviating the upper GI irritation associated with bisphosphonate therapies. These benefits simplify previously complex treatment regimens and can lead to increased patient compliance with bisphosphonate therapies.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 12/183,359,filed Jul. 31, 2008, which is a continuation-in-part of application Ser.No. 11/286,875, filed Nov. 23, 2005, which is a continuation-in-part ofapplication Ser. No. 11/106,816, filed Apr. 15, 2005, which claims thebenefit of U.S. Provisional Application No. 60/573,881, May 24, 2004,all of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to oral dosage forms of risedronatecomprising risedronate, a chelating agent for enabling administration ofrisedronate with food, and means for effecting delayed release ofrisedronate and the chelating agent in the small intestine. The oraldosage forms of the invention provide delivery of the pharmaceuticalcomposition to the small intestine of the mammal subject and providepharmaceutically effective absorption of risedronate when administeredwith or without food or beverages. The present invention further relatesto a method of treating or preventing diseases characterized by abnormalcalcium and phosphate metabolism comprising administering to a human orother mammal in need thereof the oral dosage form described herein.

BACKGROUND OF THE INVENTION

Bisphosphonates were first developed to complex calcium in hard water toimprove detergent performance. Bisphosphonates have since been found tobe useful in the treatment and prevention of diseases or conditionscharacterized by abnormal calcium and phosphate metabolism. Suchconditions may be divided into two broad categories:

-   -   1. Conditions which are characterized by anomalous mobilization        of calcium and phosphate leading to general or specific bone        loss or excessively high calcium and phosphate levels in the        fluids of the body. Such conditions are sometimes referred to        herein as pathological hard tissue demineralization.    -   2. Conditions which cause or result from deposition of calcium        and phosphate anomalously in the body. These conditions are        sometimes referred to herein as pathological calcifications.

The first category includes osteoporosis, a condition in which bone hardtissue is lost disproportionately to the development of new hard tissue.Essential quantities of cancellous bone are lost, and marrow and bonespaces become larger, resulting in reduced cancellous bone strength.Bone also becomes less dense and fragile. Osteoporosis can besub-classified as senile, drug induced (e.g., adrenocorticoid, as canoccur in steroid therapy), disease induced (e.g., arthritic and tumor),etc., however the manifestations are similar. Another condition in thefirst category is Paget's disease (osteitis deformans). In this disease,dissolution of normal bone occurs, which is then haphazardly replaced bysoft, poorly mineralized tissue such that the bone becomes deformed frompressures of weight bearing, particularly in the tibia and femur.Hyperparathyroidism, hypercalcemia of malignancy, and osteolytic bonemetastasis are conditions also included in the first category.

The second category, involving conditions manifested by anomalouscalcium and phosphate deposition, includes myositis ossificansprogressiva, calcinosis universalis, and such afflictions as arthritis,neuritis, bursitis, tendonitis, and other inflammatory conditions whichpredispose involved tissue to deposition of calcium phosphates.

Bisphosphonates tend to inhibit the resorption of bone tissue, which isbeneficial to patients suffering from excessive bone loss. However, manyof the early bisphosphonates, such as ethane-1,1-diphosphonic acid(EHDP), propane-3-amino-1-hydroxy-1,1-diphosphonic acid (APD), anddichloromethane diphosphonic acid (Cl₂MDP), have the propensity ofinhibiting bone mineralization when administered at high dosage levels.Although more biologically potent bisphosphonates exist, which can beadministered at lower dosage levels (such as1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid(risedronate), alendronate, ibandronate, and zoledronate), oraladministration of bisphosphonates sometimes results in patientcomplaints shortly after dosing. These complaints are usuallycharacterized by the patients as heartburn, esophageal burning, painand/or difficulty upon swallowing, and/or pain existing behind and/ormid-sternum. It is hypothesized that this irritation results from thebisphosphonate tablet adhering to epithelial and mucosal tissues,resulting in the topical irritation thereof. In order to avoid potentialupper gastrointestinal irritation, patients taking bisphosphonates areinstructed to take their medication with a full glass of water, and toremain upright for at least thirty minutes after taking an oral dose ofa bisphosphonate.

It is known that oral doses of bisphosphonates are poorly absorbed (lessthan 1% of the oral dose) in the gastrointestinal (GI) tract. See Ezraet al., Adv. Drug Del. Rev. 42: 175-95 (2000). Several approaches havebeen suggested for increasing absorption of oral bisphosphonatesthroughout the GI tract. These approaches include modifying thepermeability properties of the intestinal mucosa (e.g., through the useof absorption enhancers), or altering the physical or chemicalproperties of the bisphosphonate compounds themselves (e.g., throughprodrugs).

While the use of absorption enhancers, such asethylenediaminetetraacetic acid (EDTA), that increase intestinalpermeability at high doses, has been proposed as a means of increasingabsorption of oral bisphosphonates, the applicability of EDTA as anagent in human pharmacotherapy has been thought to be “impossible” inlight of the effects of EDTA on mucosal integrity. Ezra et al., Adv.Drug Del. Rev. 42: 185 (2000). Still others have concluded that the highamount of EDTA required to effect an increase in GI absorption wouldexclude the agent as a candidate for use in oral bisphosphonatetherapies. See Janner et al., Calcif. Tissue Int. 49: 280-83 (1991).

While the primary site of bisphosphonate absorption is the smallintestine, bisphosphonates such as risedronate have similar absorptionthroughout the small intestine independent of where it was delivered.See Mitchell et al., Pharm Res., Vol. 15, No. 2: 228-232 (1998). Thustargeted delivery of the bisphosphonate alone to the small intestinewould not increase absorption or efficacy of the bisphosphonate.However, others have attempted to increase the absorption ofbisphosphonates by increasing the permeability of the intestinal mucosathrough delivery of microparticles of chelating agents andbisphosphonate to the reported site of absorption (BR2001-006601).

Bisphosphonates such as risedronate and alendronate have been approvedby a number of regulatory agencies as being effective in the treatmentof various bone pathologies. However, interactions betweenbisphosphonates and foods and minerals (especially cations like calcium,magnesium, aluminum, and iron-containing foods or supplements) causeless of the bisphosphonate to be available for absorption. For example,in Mitchell et. al., Br. J. Clin. Pharmacol. 48: 536-542 (1999), it wasdemonstrated that administration of risedronate within 30 minutes of ameal reduced the amount absorbed by 50% compared to administration inthe fasting state. In order to reduce this food effect, the labeling oforal bisphosphonate products instruct patients to take their medicationat least thirty minutes or in the case of ibandronate sixty minutes,before the first food of the day, and are instructed to take theircalcium supplements at another time of the day, or on a day when theyare not taking an oral dose of a bisphosphonate. These dosinginstructions can seem complex and inconvenient to the patient, which canlead to poor patient compliance.

There is an ongoing need to develop an oral dosage form of abisphosphonate which can be taken with or without food or beverages(i.e., has pharmaceutically effective absorption regardless of food orbeverage intake), at the preference of the patient, and which does notproduce upper gastrointestinal irritation.

It has been found that an oral dosage form comprising risedronate, asufficient amount of chelating agent to bind the ions and minerals infood, and a means for effecting delayed release of risedronate and thechelating agent in the small intestine is useful in providing immediaterelease of risedronate to the small intestine, as well aspharmaceutically effective absorption of risedronate when administeredwith or without food or beverages. The oral dosage forms of the presentinvention may be taken with or without food or beverages, thussimplifying the bisphosphonate treatment therapy and leading toincreased patient compliance and convenience. Substantial reduction inthe food effect using the present invention may not only allow the newformulation to be taken with or without food, but also achieve the sameclinical benefit at a lower dose relative to known products. Further,the oral dosage forms of the invention provide for delayed release ofrisedronate and the chelating agent in the small intestine, which mayalleviate the upper gastrointestinal irritation experienced with otheroral bisphosphonate dosage forms and the need to remain upright forthirty minutes post-dose administration.

SUMMARY OF THE INVENTION

The present invention relates to an oral dosage form comprising:

-   -   (a) from about 50 mg to less than 150 mg of a bisphosphonate        selected from the group consisting of risedronate and salts        thereof;    -   (b) from about 10 mg to about 1000 mg of a chelating agent; and    -   (c) a delayed release mechanism to immediately release the        risedronate and the chelating agent in the small intestine.

The dosage forms of the present invention provide an immediate releaseof risedronate and the chelating agent to the small intestine of themammal subject and pharmaceutically effective absorption of risedronateactive ingredient when administered with or without food or beverages.

The present invention substantially alleviates the interaction betweenrisedronate and food, which interaction results in decreased absorptionof risedronate. The resulting novel oral dosage form may thus be takenwith or without food or beverages, which simplifies previously complextreatment regimens and can lead to increased patient compliance withbisphosphonate therapies and if the patients are compliant their diseasecan be better treated. The invention further alleviates the potentialfor upper gastrointestinal irritation associated with immediate releaseoral dosage forms of bisphosphonates, by delaying release of thebisphosphonate active ingredient until the bisphosphonate and thechelating agent reach the small intestine.

The present invention further relates to a method of treating orpreventing diseases characterized by abnormal calcium and phosphatemetabolism comprising administering to a human or other mammal in needthereof the oral dosage form described herein.

The oral dosage form may be continuously administered on a monthlybasis, i.e., once every thirty days or once every calendar month.

The invention further relates to a kit comprising one or more oraldosage forms of the present invention and means for facilitatingcompliance with methods of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The term “immediate release” as used herein means dissolution of thecore tablet in less than 60 minutes, when measured by standard USPdefinitions. For example, the USP specifies that all tablets andcapsules are subject, to a general dissolution standard of not less than75% of the core content is dissolved in not more than 45 minutes in 900mL of water, using the apparatus, procedures, and interpretationpresented in the United States Pharmacopeia chapter, Dissolution, page959. For this purpose, 75% is Q, and conformance is demonstrated witheither one of Apparatus 1 at 100 rpm or Apparatus 2 at 50 rpm.”

The terms “continuous” or “continuously,” as used herein, mean atregular specified intervals. For example, a continuous scheduleaccording to a dosing regimen of once monthly means that the active isgiven one time per every thirty days or one time per calendar month foran unspecified period of time or for as long as treatment is necessary.

The term “delayed release or delayed delivery,” as used herein, refersto formulating the pharmaceutical composition comprising risedronate andthe chelating agent so that their release will be accomplished at somegenerally predictable location in the small intestine more distal tothat which would have been accomplished had there been no alteration inthe delivery of the risedronate and the chelating agent.

The term “nutrient,” as used herein, means any nutritional or dietarysupplement including but not limited to vitamins, minerals, amino acids,herbs or other botanicals, or concentrates, metabolites, constituents,extracts, or combinations of the same.

The term “pharmaceutical composition,” as used herein, means an oraldosage form comprised of a safe and effective amount of risedronate andone or more pharmaceutically-acceptable excipients including at leastone chelating agent. The pharmaceutical compositions described hereinare comprised of from 0.5% to 75%, preferably from 1% to 40% ofrisedronate and from 25% to 99.5%, preferably from 60% to 99% ofpharmaceutically-acceptable excipients including at least one chelatingagent.

The term “safe and effective amount,” as used herein, means an amount ofa compound or composition high enough to significantly positively modifythe symptoms and/or condition to be treated, but low enough to avoidserious side effects (at a reasonable risk/benefit ratio), within thescope of sound medical judgment. The safe and effective amount of activeingredient for use in the method of the invention herein will vary withthe particular condition being treated, the age and physical conditionof the patient to be treated, the severity of the condition, theduration of the treatment, the nature of concurrent therapy, theparticular active ingredient being employed, the particularpharmaceutically-acceptable excipients utilized, and like factors withinthe knowledge and expertise of the attending physician.

The term “pharmaceutically effective absorption” as used herein means anamount of a chelating compound high enough to significantly bind themetal ions and minerals in food but low enough not to significantlyalter absorption of risedronate as compared to absorption in the fastedstate. That is, absorption is similar with or without food. Given thehigh variability of bisphosphonate absorption, fed exposure within about50% of fasting exposure is expected to be pharmaceutically effectiveabsorption.

The term “oral dosage form,” as used herein, means any pharmaceuticalcomposition intended to be delivered or released to the small intestineof a human or other mammal via the mouth of said human or other mammal.

The term “unit dose” or “unit dosage” means a dosage form containing anamount of pharmaceutical active or nutrient suitable for administrationin one single dose, according to sound medical practice. The presentinvention is particularly useful for the administration of unit doses inthe form of tablets and capsules.

The term “gastrointestinal tract” or “GI tract,” as used herein, relatesto the alimentary canal, i.e., the musculo-membranous tube about thirtyfeet in length, extending from the mouth to the anus. The term “uppergastrointestinal tract,” as used herein, means the buccal cavity, thepharynx, the esophagus, and the stomach. The term “lowergastrointestinal tract,” as used herein, means the small intestine andthe large intestine.

The term “small intestine,” as used herein, means the part of the smallintestine consisting of just distal to the stomach (the duodenum, thejejunum, and the ileum), i.e., that portion of the intestinal tract justdistal to the duodenal sphincter of the fundus of the stomach andproximal to the large intestine. The term “large intestine,” as usedherein, means the part of the lower gastrointestinal tract including theascending colon, the transverse colon, the descending colon, the sigmoidcolon, and the rectum

Risedronate

The terms “bisphosphonate” and “diphosphonate,” as used herein, includeacids, salts, esters, hydrates, polymorphs, hemihydrates, solvates, andderivatives thereof. The bisphosphonates of the present inventioninclude those forms of1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid(risedronate) as described in U.S. Pat. No. 5,583,122, to Benedict etal., issued Dec. 10, 1996; U.S. Pat. No. 6,410,520 B2, to Cazer et al.,issued Jun. 25, 2002

Non-limiting examples of salts useful herein include those selected fromthe group consisting of alkali metal, alkaline metal, ammonium, andmono-, di-, tri-, or tetra-C₁-C₃₀-alkyl-substituted ammonium. Preferredsalts are those selected from the group consisting of sodium, potassium,and ammonium salts.

Mixed nomenclature is currently in use by those of ordinary skill in theart, for example reference to a specific weight or percentage of abisphosphonate active ingredient is on an anhydrous monosodium saltbasis for risedronate. As an example, the phrase “about 100 mg ofrisedronate, pharmaceutically acceptable salts thereof, and mixturesthereof, on an anhydrous monosodium salt basis” means that the amount ofthe risedronate compound selected is calculated based on about 100 mg ofanhydrous risedronate monosodium salt.

As is discovered herein, substantial reduction in the food effect usingthe present invention may not only allow the new formulation to be takenwith or without food, but also achieve the same clinical benefit at alower dose relative to known products. The oral dosage form containsfrom about 50 mg to less than 150 mg of the risedronate, alternativelyfrom about 75 to about 125 mg of the risedronate, and alternativelyabout 100 mg of the risedronate (all on a risedronate anhydrousmonosodium salt basis).

Chelating Agent

The term “chelating agent,” as used herein, means a molecule containingtwo or more electron donor atoms that can form coordinate bonds to asingle metal ion. The term “chelating agent” is understood to includethe chelating agent as well as salts thereof. For example, the term“chelating agent” includes citric acid as well as its salt forms.

The most common and widely used chelating agents coordinate to metalatoms through oxygen or nitrogen donor atoms, or both. Other less commonchelating agents coordinate through sulfur in the form of —SH (thiol ormercapto) groups. After the first coordinate bond is formed, eachsuccessive donor atom that binds creates a ring containing the metalatom. A chelating agent may be bidentate, tridentate, tetradentate,etc., depending upon whether it contains two, three, four, or more donoratoms capable of binding to the metal atom. See Kirk-Othmer Encyclopediaof Chemical Technology (4th ed. 2001).

In homogeneous dilute solutions, the equilibrium constant for theformation of the complex from the solvated metal ion (e.g., calcium) andthe chelating agent in its fully dissociated form is called theformation or stability constant, K. The practical significance offormation constants is that a high log K value means a large ratio ofchelated to unchelated (or free) metal ion, when equivalent amounts ofmetal ion and chelating agent are present. Higher ratios (or differenceif K is expressed in log units) of the chelating agent and thebisphosphonate complexation constants are preferred in order to havenearly all of the metal ion complexed to the chelating agent instead ofthe bisphosphonate. For example, for equal molar amounts of bothbisphosphonate and the chelating agent, in order for the metal ions tobe 99% complexed to the chelating agent, the chelating agent must have alog K which is at least 4 units higher than the bisphosphonate-metal ioncomplex. The other technique which can be used to favor the chelatingagent-metal ion complex over that of the bisphosphonate-metal ioncomplex is to add a molar excess of the chelating agent which relies onthe law of mass action to favor formation of the chelating agent-metalion complex.

Although pH and solution concentration can affect the formationconstant, in general, the log K of the chelating agent is preferably atleast equal to that of the bisphosphonate. In other instances the log Kof the chelating agent is 2 to 5 units higher than that of thebisphosphonate. In other instances, the chelating agent is present at amolar excess to that of the bisphosphonate. The chelating agent in suchinstances is present in at least a 2:1 molar ratio of the chelatingagent to bisphosphonate.

In one embodiment, the chelating agent is selected from the groupconsisting of sodium or disodium EDTA, citric acid, malic acid, tartaricacid, lactic acid, adipic acid, succinic acid, lysine, sodiumhexametaphosphate, and combinations thereof. In another embodiment, thechelating agent is sodium or disodium EDTA, citric acid, or sodiumhexametaphosphate.

The amount of chelating agent present in the oral dosage form of thepresent invention will depend on the particular chelating agent oragents (i.e., mixtures of chelating agents) selected, the amount ofbisphosphonate active ingredient present in the oral dosage form, andthe specific portion of the small intestine where delivery and releaseof the chelating agent and/or bisphosphonate active ingredient isdesired. After the ingestion of milk, it has been shown in the art thatthe concentration of calcium decreases over the length of the lower GItract, beginning with the small intestine and proceeding through to theend of the small intestine. Mahe, J. et al., Gastroileal nitrogen andelectrolyte movements after bovine milk ingestion in humans, Am. J.Clin. Nutr. 56: 410-16 (1992).

The concentration of calcium in the stomach is approximately 10-foldhigher than that of the concentration in the jejunum and approximately40 times that in the ileum. Thus if the risedronate and chelating agentwere released in the stomach (with food), the amount of chelating agentwould be insufficient to overcome the effect of calcium on drugabsorption. The concentration of calcium in the jejunum and ileum arelower and by targeting release of the dosage form in these regions wherethe amount of calcium is lower, the chelating agent is more effective atbinding most or all of the calcium than if released in the stomach. Itis also desirable to target release of the tablet in the small intestineand after the coating dissolves and releases the chelating agent andrisedronate from the core tablet in an immediate release fashion. Thiswill maximize the local concentration of the chelant in relationship tothat of the calcium in the small intestine. Slow or prolonged deliveryof the chelating agent in the small intestine is not anticipated toachieve the desired local concentration of the chelating agent and thistype of delivery will not overcome the food effect.

Generally, the oral dosage forms of the present invention will contain asafe and effective amount of a chelating agent suitable for achievingthe desired chelating effect, that is, chelating the residual metal ionsthat are present in the gastrointestinal tract from food at the site ofdelivery without significantly affecting the absorption of thebisphosphonate had no food been present. In one embodiment, the oraldosage form contains from about 10 mg to about 1000 mg of a chelatingagent. In another embodiment, the oral dosage forms contain from about10 mg to about 500 mg of a chelating agent. When the chelating agent isdisodium EDTA, an optional range is from about 55 mg to about 500 mg,alternatively from about 75 mg to about 250 mg, alternatively from about75 mg to about 150 mg, alternatively about 100 mg. When the chelatingagent is citric acid, an optional range is from about 100 mg to about970 mg, alternatively from about 250 mg to about 500 mg per unit dose.

Delayed Delivery to the Small Intestine

The ultimate site of and/or the rate of delivery in the small intestinecan be satisfactorily controlled by one skilled in the art, bymanipulating any one or more of the following:

-   -   (a) the active ingredient proper;    -   (b) the type and level of disintegrant;    -   (c) the type of coating, the type and level of excipients added        to the coating and the concomitant desirable thickness and        permeability (swelling properties) of the coating;    -   (d) the time dependent conditions of the coating itself and/or        within the coated tablet, particle, bead, or granule;    -   (e) the particle size of the granulated active ingredient;    -   (f) the pH dependent conditions of the coating itself and/or        within the coated tablet, particle, bead, or granule;    -   (g) the particle size or solubility of the chelating agent;    -   (h) the dissolution rate of the coating;    -   (j) size or shape of the tablet.

In addition the pharmacodynamic effect of the tablets, after multipledosing, should be within at least 75% of the comparable immediaterelease tablet.

Delayed Release in the Small Intestine

A human or other mammal suffering from diseases or disorders involvingcalcium and phosphate metabolism can be successfully treated by thedelivery of risedronate to the small intestine of said human or othermammal. The novel dosage forms described herein effect an immediaterelease to the small intestine, and prohibit the undesired release ofrisedronate in the mouth, pharynx, esophagus, and/or stomach, therebyprohibiting the erosion, ulceration, or other like irritation of theepithelial or mucosal layers of these tissues.

The chelant and risedronate are released rapidly and as close tosimultaneously as possible. This causes the local concentration ofchelating agent to be higher in relationship to the metal ions in thefood. The higher local concentration of chelating agent in theenvironment where the active is released may more effectively complexthe metals in the food and facilitate absorption of the bisphosphonate.This can be conveniently achieved from a single tablet.

Various means for targeting release of risedronate and the chelatingagent in the small intestine are suitable for use in the presentinvention. Non-limiting examples of means for delivery to the smallintestine include pH triggered delivery systems and time dependentdelivery systems.

pH Triggered Delivery Systems

One embodiment of the present invention involves coating (or otherwiseencapsulating) the risedronate and the chelating agent(s) with asubstance which is not broken down, by the gastrointestinal fluids torelease the risedronate and the chelating agent until a specific desiredpoint in the intestinal tract is reached. In one embodiment, delayedrelease of the pharmaceutical composition is achieved by coating thetablet, capsule, particles, or granules, of the risedronate and thechelating agent with a substance which is pH dependent, i.e., brokendown or dissolves at a pH which is generally present in the smallintestine, but not present in the upper GI tract (i.e., the mouth,buccal cavity, pharynx, esophagus, or stomach) or lower GI tract.

In some cases, it may be desirable that the risedronate and thechelating agent are released at a particular location in the smallintestine. In other cases, it may be desirable to release therisedronate and the chelating agent independently at different locationswithin the small intestine. For example, it may be desirable to releasethe chelating agent in the, jenunum and the risedronate in the ileum.When targeted release of the risedronate and the chelating agenttogether or separately in particular locations within the smallintestine is desired, the selection of the coating material and/or themethod of coating or otherwise combining the risedronate and thechelating agent with the selected coating material or otherpharmaceutically-acceptable excipients may be varied or altered as isdescribed herein, or by any method known to one skilled in the art.

Solubility, acidity, and susceptibility to hydrolysis of the differentrisedronate active ingredients, such as acid addition salts, saltsformed with the phosphonic group (e.g., alkali metal salts, alkalineearth metal salts, etc.), and esters (e.g., alkyl, alkenyl, aryl,arylalkyl) may be used as guidelines for the proper choice of coating.In addition, suitable pH conditions might be established within thecoated tablets, particles, or granules by adding a suitable buffer tothe active ingredient in accordance with the desired release pattern.

One embodiment of the present invention is delivered to the smallintestine utilizing a pH dependent enteric coating material made from apartly methyl esterified methacrylic acid polymer. The oral dosage formcan be in the form of an enteric coated compressed tablet made ofgranules or particles of active ingredient.

Any enteric coating which is insoluble at a pH below 5.5 (i.e., thatgenerally found in the mouth, pharynx, esophagus, and stomach), butsoluble between about pH 5.5 and about pH 6.5 (i.e., that present in thesmall intestine) can be used in the practice of the present invention.Accordingly, when it is desired to effect delivery of the bisphosphonateand the chelating agent to the small intestine, any enteric coating issuitable which is wholly- or partially-insoluble at a pH below 5.5 andsoluble at about a pH 5.5 to about pH 6.5.

The enteric coating must be applied to the compressed tablet, or capsule(e.g., gelatin, starch, or hydroxypropylmethylcellulose) in a sufficientthickness so that the entire coating does not dissolve ingastrointestinal fluids at a pH below 5.5, but does dissolve at a pHabove about 5.5 and below pH about 6.5 The dissolution or disintegrationof the excipient coating generally does not occur until the entry of thecoated dosage form into the small intestine.

It is expected that any anionic polymer exhibiting the requisitepH-dependent solubility profile can be used as an enteric coating in thepractice of the present invention to achieve delivery of thebisphosphonate and chelating agent to the small intestine. The coatingchosen must be compatible with the particular risedronate activeingredient selected. The preferred polymers for use in the presentinvention are anionic carboxylic polymers. It is particularly preferredthat the polymers are acrylic polymers, more preferably partlymethyl-esterified methacrylic acid polymers, in which the ratio of freeanionic carboxyl groups to ester groups is about 1:1.

A particularly suitable methacrylic acid copolymer is Eudragit L®,particularly Eudragit L 30 D-55® and Eudragit L 100-55®, manufactured byRöhm Pharma GmbH and Co. KG, Darmstadt, Germany. In Eudragit L 30 D-55®,the ratio of free carboxyl groups to ester groups is approximately 1:1.Further, said copolymer is known to be insoluble in GI fluids having apH below 5.5, generally 1.5-5.5, i.e., that generally present in thefluid of the upper GI tract, but readily soluble at pH above 5.5, i.e.,that generally present in the fluid of the small intestine.

The coating can, and usually will, contain a plasticizer and possiblyother coating excipients such as coloring agents, surfactant, talc,and/or magnesium stearate, many of which are well known in the coatingart. In particular, anionic carboxylic acrylic polymers usually willcontain 10-25% by weight of a plasticizer, especially triethyl citrate,tributyl citrate, acteyltriethyl citrate, dibutyl phthalate, diethylphthalate, polyethylene glycol, acetylated monoglycerides propyleneglycol, and triacetin. Conventional coating techniques such as fluid-bedor pan coating are employed to apply the coating. Coating thickness mustbe sufficient to ensure that the oral dosage form remains essentiallyintact until the desired site of delivery in the small intestine isreached.

The solid oral dosage form may be in the form of a coated compressedtablet which contains particles or granules of the bisphosphonate activeingredient and the chelating agent, or of a soft or hard capsule (e.g.,gelatin, starch, or hydroxypropylmethylcellulose), coated or uncoated,which contains beads or particles of the bisphosphonate activeingredient and the chelating agent, which themselves are entericallycoated. In an embodiment of the invention the tablets are compressed andthe tablet is enteric coated.

Suitable enteric coating materials include Eudragit L-100®, Eudragit L30 D-55®, cellulose acetate phthalate, shellac, or any enteric coatingmaterial that dissolves at about pH 5.5 to about 6.5. The entericcoating is applied using various spray techniques known to one skilledin the art. The enteric coating may further comprise one or morepharmaceutically-acceptable excipients including, but not limited to,talc, triethyl citrate, polyethylene glycol, Tween 80® (polyoxyethylenesorbitan monooleate, available from Sigma Chemical CO., St. Louis, Mo.),castor oil. The enteric coating is applied to the tablet core to providea weight gain of 2.5% to 40%.

The tablet core comprises a bisphosphonate active ingredient, achelating agent, and may contain one or more pharmaceutically-acceptableexcipients. Suitable excipients include, but are not limited to,crystalline cellulose, lactose, calcium hydrogen phosphate,polyvinylpyrrolidone, magnesium stearate, sucrose, starch, magnesiumoxide, sodium starch glycolate and sodium lauryl sulfate.

Time Dependent Delivery Systems

In another embodiment of the invention, delivery of the risedronate andthe chelating agent to the small intestine is achieved through the useof a time dependent delivery system. Given established transit timesafter gastric emptying, drug and/or chelating agent release can betargeted to the various segments of the small intestine. Approaches totime dependent delivery systems suitable for use in the presentinvention include, but are not limited to, such devices as thePulsincap™ (Scherer DDS, Strathclyde, U.K.), the Time Clock™ (ZambonGroup, Milan, Italy), and SyncroDose™ (Penwest, Patterson, N.Y.), aswell as various coatings which degrade over time to release tabletcontents such as hydroxypropylmethylcellulose, hydroxypropylcellulose,or any suitable hydrogel.

In one embodiment of the invention, the time-dependent device Pulsincap™is used to target delivery of the active ingredient and the chelatingagent to the small intestine. The active ingredient and otherexcipients, including the chelating agent, are contained inside thePulsincap™ water-insoluble capsule by means of a hydrogel plug which iscovered by a water-soluble cap. The entire dose form is optionallycoated in an enteric-coating material to protect the dose form fromdegradation while in transit through the upper GI tract. When thepatient swallows the Pulsincap™ dosage form, the water-soluble capdissolves and exposes the hydrogel plug to gastric and/or intestinalfluids. The hydrogel cap then swells, and eventually pops out of thecapsule body, thus releasing the capsule contents. Release of thecapsule contents can be targeted to specific regions of the smallintestine by modifying the hydrogel plug properties. Watts, Peter J. &Illum, Lisbeth, Drug Dev. and Indus. Pharm., 23(9): 893-917 (1997).

In one embodiment of the invention, a time dependent coating is appliedover a compressed tablet and then an enteric coating is applied over thetime dependent coating. This is used to target delivery of the activeingredient and the chelating agent to the small intestine. The activeingredient and other excipients, including the chelating agent, arecontained inside the core tablet. The entire dose form is coated with atime dependent coating and then an enteric coating. The enteric-coatingmaterial is to protect the dose form from degradation while in transitthrough the upper GI tract. When the patient swallows the dosage formthe enteric coating dissolves after the dosage form leaves the stomachand then the core tablet starts to swell. Eventually, at a predeterminedtime in the small intestine fluids, the time dependent coating willrupture and releases the contents of the core tablet in the smallintestine. Release of the core tablet contents can be targeted tospecific regions of the small intestine by modifying the core tablet,time dependent coating and/or the enteric coating.

Pharmaceutically-Acceptable Excipients

Pharmaceutically-acceptable excipients include, but are not limited to,polymers, resins, plasticizers, fillers, lubricants, diluents, binders,disintegrants, solvents, co-solvents, surfactants, buffer systems,preservatives, sweetener agents, flavoring agents, pharmaceutical-gradedyes or pigments, chelating agents, viscosity agents, and combinationsthereof. Pharmaceutically-acceptable excipients can be used in anycomponent in making the oral dosage form, i.e. core tablet or coating.

Flavoring agents and dyes and pigments among those useful herein includebut are not limited to those described in Handbook of PharmaceuticalExcipients (4th Ed., Pharmaceutical Press 2003).

Suitable co-solvents include, but are not limited to, ethanol,isopropanol, and acetone.

Suitable surfactants include, but are not limited to, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrosemonoesters, simethicone emulsion, sodium lauryl sulfate, Tween 80®, andlanolin esters and ethers.

Suitable preservatives include, but are not limited to, phenol, alkylesters of parahydroxybenzoic acid, benzoic acid and the salts thereof,boric acid and the salts thereof, sorbic acid and the salts thereof,chlorbutanol, benzyl alcohol, thimerosal, phenylmercuric acetate andnitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride,methyl paraben, and propyl paraben.

Suitable fillers include, but are not limited to, starch, lactose,sucrose, maltodextrin, and microcrystalline cellulose.

Suitable plasticizers include, but are not limited to, triethyl citrate,polyethylene glycol, propylene glycol, dibutyl phthalate, castor oil,acetylated monoglycerides, and triacetin.

Suitable polymers include, but are not limited to, ethylcellulose,cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate,cellulose acetate phthalate, polyvinyl acetate phthalate, and Eudragit®L 30-D, Eudragit® L 100-55, (Röhm Pharma GmbH and Co. KG, Darmstadt,Germany), and Acryl-EZE® and Sureteric® (Colorcon, Inc., West Point,Pa.).

Suitable lubricants include, but are not limited to, magnesium stearate,stearic acid, and talc.

Methods of Use

The present invention further relates to a method of treating orpreventing diseases characterized by abnormal calcium and phosphatemetabolism comprising administering to a human or other mammal in needthereof a safe and effective amount of a pharmaceutical compositiondelivered to said human or other mammal via the oral dosage formsdescribed herein.

Diseases characterized by abnormal calcium and phosphate metabolisminclude, but are not limited to, osteoporosis, Paget's disease (osteitisdeformans), hyperparathyroidism, hypercalcemia of malignancy, osteolyticbone metastasis, myositis ossificans progressiva, calcinosisuniversalis, and such afflictions as arthritis, neuritis, bursitis,tendonitis, and other inflammatory conditions which predispose involvedtissue to deposition of calcium phosphates.

The oral dosage forms of the present invention are suitable foradministration to a patient according to a continuous monthly dosinginterval.

Kits

The present invention further comprises kits that are particularlyuseful for administering the oral dosage forms described hereinaccording to a monthly continuous dosing schedule. Such kits compriseone or more oral dosage forms comprising risedronate (or salt) and achelating agent and a means for facilitating compliance with methods ofthis invention. Such kits provide a convenient and effective means forassuring that the subject to be treated takes the appropriate oraldosage form in the correct dosage and in the correct manner. Thecompliance means of such kits includes any means which facilitatesadministering the active according to a method of this invention. Suchcompliance means includes instructions, packaging, and dispensing means,and combinations thereof. The kits can also comprise a means for aidingthe memory, including but not limited to a listing of the days of theweek, numbering, illustrations, arrows, Braille, calendar stickers,reminder cards, or other means specifically selected by the patient.Examples of packaging and dispensing means are well known in the art,including those described in U.S. Pat. No. 4,761,406, Flora et al.,issued Aug. 2, 1988; and U.S. Pat. No. 4,812,311, Uchtman, issued Mar.14, 1989.

Optionally, the kits can comprise at least one oral dosage formcomprising a risedronate and a chelating agent and at least one oraldosage form of an accompanying nutrient. Preferred nutrients are calciumand/or vitamin D. Oral forms of calcium suitable for use in the presentinvention include capsules, compressed tablets, chewable tablets, andthe like. Typical salt forms of calcium suitable for use in the presentinvention include but are not limited to calcium carbonate, calciumcitrate, calcium malate, calcium citrate malate, calcium glubionate,calcium gluceptate, calcium gluconate, calcium lactate, dibasic calciumphosphate, and tribasic calcium phosphate. In one embodiment, kits ofthe present invention may include tablets comprising 400 mg to 1500 mgcalcium.

The term “vitamin D,” as used herein, refers to any form of vitamin Dthat may be administered to a mammal as a nutrient. Vitamin D ismetabolized in the body to provide what is often referred to as“activated” forms of vitamin D. The term “vitamin D” can includeactivated and non-activated forms of vitamin D, as well as precursorsand metabolites of such forms. Precursors of these activated formsinclude vitamin D₂ (ergocalciferol, produced in plants) and vitamin D₃(cholecalciferol, produced in skin and found in animal sources and usedto fortify foods). Vitamins D₂ and D₃ have similar biological efficacyin humans. Non-activated metabolites of vitamins D₂ and D₃ includehydroxylated forms of vitamins D₂ and D₃. Activated vitamin D analogscannot be administered in large doses on an intermittent schedule, dueto their toxicity in mammals. However, non-activated vitamin D₂, vitaminD₃, and their metabolites may be administered in larger doses than“active” forms of vitamin D on an intermittent basis, without toxicity.In one embodiment, kits of the present invention may include tabletscomprising 100 IU to 10,000 IU of vitamin D.

In another embodiment, kits of the present invention may include one ormore nutrient tablets comprising both calcium and vitamin D. In afurther embodiment, the unit dose of nutrient comprises about 600 mgcalcium and about 400 IU vitamin D.

The following non-limiting examples illustrate the formulations,processes, and uses of the present invention.

EXAMPLES Example I Enteric-Coated Tablets Containing Risedronate andEDTA

Enteric-coated tablets containing risedronate and EDTA are made bypreparing a coating composition and compressed tablets containingrisedronate and EDTA, and then applying said coating composition to saidtablets.

An enteric coating composition is prepared in the form of a lacquercontaining the following excipients, per tablet:

A. Enteric Coating Suspension

Ingredients: Eudragit L 30 D-55 ® (wet basis) (manufactured by 73.65 mgRöhm Pharma GmbH and Co. KG, Darmstadt, Germany) Triethylcitrate 2.21 mgTalc 16.57 mg Yellow Iron Oxide 0.03 mg Simethicone 0.07 mg Polysorbate80 0.22 mg Purified Water 113.2 mg

The enteric coating is prepared using the following method:

A pigment suspension is prepared by adding polysorbate 80, ground ferricoxide, and talc to approximately three-quarters of the purified waterwhile mixing. The suspension is mixed for at least 60 minutes. Thesimethicone and the remaining water are added to the pigment suspensionand mixed for at least 60 minutes. The Eudragit L 30 D-55 is screenedthen combined with triethyl citrate and mixed for at least 45 minutes.The pigment suspension is then added to the Eudragit solution and mixedfor 30 to 60 minutes. The resulting coating suspension is mixedthroughout the coating process. The core tablets are transferred to thecoating pan and preheated with occasional jogging. Tablets are coated,using a typical pan coating process until the required quantity ofcoating solution has been applied. Tablets are then cooled and collectedin suitable containers.

A coating weight gain of 10% (total solids) is applied by spraying theabove composition onto compressed tablets containing risedronate andEDTA, prepared in Part B below.

B. Compressed Tablets Containing Risedronate and EDTA

The enteric coating suspension prepared in Part A above is sprayed onto75 mg risedronate tablets, each tablet weighing 390 mg and eachcontaining:

Active Ingredients: Risedronate Sodium 75 mg* Chelant: Disodium EDTA 100mg Excipients Prosolv SMCC 90 181.8 mg Sodium starch glycolate 9.7 mgStearic acid 19.5 mg Magnesium stearate 3.9 mg *This amount iscalculated on a risedronate anhydrous monosodium salt basis.

Tablets having the composition set forth above are prepared as follows:

Pass the edetate disodium, risedronate sodium, and ProSolv SMCC 90through a mill and transfer to a blender equipped with an intensifierbar. Blend with intensifier bar on for 10 minutes. Pass the sodiumstarch glycolate through a mill and add to the blender. Blend for 8minutes with the intensifier bar off. The stearic acid and magnesiumstearate are screened and added to the blender. The blend is mixed forapproximately 3 minutes with the intensifier bar off. The blend iscompressed into tablets using a suitable tablet press.

Example II Enteric-Coated Tablets Containing Risedronate and EDTA

Enteric-coated tablets containing risedronate and EDTA are made bypreparing a coating composition and compressed tablets containingrisedronate and EDTA, and then applying said coating composition to saidtablets.

An enteric coating composition is prepared in the form of a lacquercontaining the following excipients, per tablet:

A. Enteric Coating Suspension

Ingredients: Eudragit L 30 D-55 ® (wet basis) (manufactured by 77.34 mgRöhm Pharma GmbH and Co. KG, Darmstadt, Germany) Triethylcitrate 2.32 mgTalc 17.4 mg Yellow Iron Oxide 0.03 mg Simethicone 0.07 mg Polysorbate80 0.23 mg Purified Water 118.88 mg

The enteric coating is prepared using the following method:

A pigment suspension is prepared by adding polysorbate 80, ground ferricoxide, and talc to approximately three-quarters of the purified waterwhile mixing. The suspension is mixed for at least 60 minutes. Thesimethicone and the remaining water are added to the pigment suspensionand mixed for at least 60 minutes. The Eudragit L 30 D-55 is screenedthen combined with triethyl citrate and mixed for at least 45 minutes.The pigment suspension is then added to the Eudragit solution and mixedfor 30 to 60 minutes. The resulting coating suspension is mixedthroughout the coating process. The core tablets are transferred to thecoating pan and preheated with occasional jogging. Tablets are coated,using a typical pan coating process until the required quantity ofcoating solution has been applied. Tablets are then cooled and collectedin suitable containers.

A coating weight gain of 10% (total solids) is applied by spraying theabove composition onto compressed tablets containing risedronate andEDTA, prepared in Part B below.

B. Compressed Tablets Containing Risedronate and EDTA

The enteric coating suspension prepared in Part A above is sprayed onto100 mg risedronate tablets, each tablet weighing 440 mg and eachcontaining:

Active Ingredients: Risedronate Sodium 100 mg* Chelant: Disodium EDTA100 mg Excipients Prosolv SMCC 90 202.6 mg Sodium starch glycolate 11 mgStearic acid 22 mg Magnesium stearate 4.4 mg *This amount is calculatedon a risedronate anhydrous monosodium salt basis.

Tablets having the composition set forth above are prepared as follows:

Pass the edetate disodium, risedronate sodium, and ProSolv SMCC 90through a mill and transfer to a blender equipped with an intensifierbar. Blend with intensifier bar on for 10 minutes. Pass the sodiumstarch glycolate through a mill and add to the blender. Blend for 8minutes with the intensifier bar off. The stearic acid and magnesiumstearate are screened and added to the blender. The blend is mixed forapproximately 3 minutes with the intensifier bar off. The blend iscompressed into tablets using a suitable tablet press.

Example III Enteric-Coated Tablets Containing Risedronate and EDTA

Enteric-coated tablets containing risedronate and EDTA are made bypreparing a coating composition and compressed tablets containingrisedronate and EDTA, and then applying said coating composition to saidtablets.

An enteric coating composition is prepared in the form of a lacquercontaining the following excipients, per tablet:

A. Enteric Coating Suspension

Ingredients: Eudragit L 30 D-55 ® (wet basis) (manufactured by 77.34 mgRöhm Pharma GmbH and Co. KG, Darmstadt, Germany) Triethylcitrate 2.32 mgTalc 17.4 mg Yellow Iron Oxide 0.03 mg Simethicone 0.07 mg Polysorbate80 0.23 mg Purified Water 118.88 mg

The enteric coating is prepared using the following method:

A pigment suspension is prepared by adding polysorbate 80, ground ferricoxide, and talc to approximately three-quarters of the purified waterwhile mixing. The suspension is mixed for at least 60 minutes. Thesimethicone and the remaining water are added to the pigment suspensionand mixed for at least 60 minutes. The Eudragit L 30 D-55 is screenedthen combined with triethyl citrate and mixed for at least 45 minutes.The pigment suspension is then added to the Eudragit solution and mixedfor 30 to 60 minutes. The resulting coating suspension is mixedthroughout the coating process. The core tablets are transferred to thecoating pan and preheated with occasional jogging. Tablets are coated,using a typical pan coating process until the required quantity ofcoating solution has been applied. Tablets are then cooled and collectedin suitable containers.

A coating weight gain of 10% (total solids) is applied by spraying theabove composition onto compressed tablets containing risedronate andEDTA, prepared in Part B below.

B. Compressed Tablets Containing Risedronate and EDTA

The enteric coating suspension prepared in Part A above is sprayed onto125 mg risedronate tablets, each tablet weighing 495 mg and eachcontaining:

Active Ingredients: Risedronate Sodium 125 mg* Chelant: Disodium EDTA100 mg Excipients Prosolv SMCC 90 227.9 mg Sodium starch glycolate 12.35mg Stearic acid 24.75 mg Magnesium stearate 4.95 mg *This amount iscalculated on a risedronate anhydrous monosodium salt basis.

Tablets having the composition set forth above are prepared as follows:

The risedronate sodium, edetate disodium, sodium starch glycolate, andProSolv SMCC 90 are passed through a mill and added to a blenderequipped with an intensifier bar. The mixture is blended forapproximately ten minutes with the intensifier bar on. The stearic acidand magnesium stearate are screened and added to the blender. The blendis mixed for approximately 3 minutes with the intensifier bar off. Theblend is compressed into tablets using a suitable tablet press.

Example IV

A 65 kg woman diagnosed with postmenopausal osteoporosis is prescribedthe enteric-coated oral dosage form of Example I, to be taken oncemonthly.

Example V

A 70 kg man diagnosed with prostate cancer and high bone turnover isprescribed the enteric-coated oral dosage form of Example II, to betaken once monthly. The patient takes the oral dosage form once permonth, immediately before going to sleep. The patient does notexperience upper GI irritation or discomfort.

Example VI

A group of women diagnosed with postmenopausal osteoporosis areprescribed the enteric-coated oral dosage form of Example III, to betaken once monthly, comprising 100 mg risedronate sodium. The patientstake the oral dosage form with breakfast once per month.

All documents cited are, in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

What is claimed is:
 1. An oral dosage form comprising: (a) from about 50mg to about 125 mg of a bisphosphonate selected from the groupconsisting of risedronate and salts thereof; (b) from about 10 mg toabout 1000 mg of ethylenediaminetetraacetate (EDTA) or apharmaceutically acceptable salt thereof; and (c) a delayed releasemechanism to immediately release the bisphosphonate and the EDTA orpharmaceutically acceptable salt thereof in the small intestine.
 2. Theoral dosage form of claim 1 wherein the bisphosphonate is risedronatesodium.
 3. The oral dosage form of claim 2 wherein the EDTA is disodiumEDTA.
 4. The oral dosage form of claim 2 wherein the delayed releasemechanism is selected from the group consisting of pH triggered deliverysystems, time dependent delivery systems and mixtures thereof.
 5. Theoral dosage form of claim 4 wherein the delayed release mechanism is apH triggered delivery system.
 6. The oral dosage form of claim 5 whereinthe pH triggered delivery system comprises an enteric coating.
 7. Theoral dosage form of claim 6 wherein the enteric coating comprisesmethacrylic acid copolymer.
 8. The oral dosage form of claim 7comprising from about 55 mg to about 500 mg of the disodium EDTA.
 9. Theoral dosage form of claim 8 comprising from about 75 mg to about 250 mgof the disodium EDTA.
 10. The oral dosage form of claim 9 comprisingabout 100 mg of the risedronate sodium.
 11. The oral dosage form ofclaim 9 wherein the delayed release mechanism comprises a methacrylicacid copolymer.
 12. The oral dosage form of claim 11 comprising about100 mg of the risedronate sodium.
 13. The oral dosage form of claim 12comprising about 100 mg of the disodium EDTA.
 14. The oral dosage formof claim 9 comprising about 75 mg of the risedronate sodium.
 15. Theoral dosage form of claim 11 comprising about 75 mg of the risedronatesodium.
 16. The oral dosage form of claim 15 comprising about 100 mg ofdisodium EDTA.
 17. The oral dosage form of claim 16, wherein themethacrylic acid copolymer is poly (methacylic acid, ethyl acrylate)1:1.
 18. The oral dosage form of any one of claims 6, 7, 11, 13 and 14to 17, wherein the enteric coating does not entirely dissolve ordisintegrate until the dosage form enters the small intestine.
 19. Theoral dosage form of claim 18, wherein the enteric coating dissolves at apH of about 5.5 or above and below a pH of about 6.5.